Any one individual is at risk of developing cancer. The occurrence of cancer increases with aging over a life time (“lifetime risk”). For example, in the U.S., men have a 1 in 2 lifetime risk of developing cancer, and women have a 1 in 3 risk. Other risk factors are believed to include genetics, diet, and environmental exposure (e.g., to mutagenic chemicals, radiation, transforming viruses, etc.). It is estimated by the World Health Organization that about 10 million new cancer cases are occurring now annually around the world. That number is expected to reach 15 million by the year 2015, with two thirds of these new cases occurring in developing countries (World Health 48:22, 1995). For example, it is estimated that there is about 600,000 new cases of lung cancer per year worldwide; approaching 1 million new cases of breast cancer per year; and for head and neck cancer (the sixth most frequently occurring cancer worldwide) an incidence of 500,000 new cases annually. The National Cancer Institute of the United States estimates the overall annual costs for cancer at $107 billion. Treatment costs account for approximately $40 billion.
Several chemotherapeutic agents are in use in the treatment of cancer, including alkylating agents, antimetabolites antagonists, anticancer antibiotics, and plant-derived anticancer agents. Examples of “alkylating agents” include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, carboquone, adozelesin, cystemustine, and bizelesin. Examples of “antimetabolites” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emmitefur), aminopterine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine, and ambamustine, etc. Examples of “anticancer antibiotics” include actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, and idarubicin hydrochloride, etc. Examples of “plant-derived anticancer agents” include etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, and vinorelbine, etc.
While new therapeutics are being developed and tested for efficacy against tumors, many of the currently available cancer treatments are relatively ineffective. It has been reported that chemotherapy results in a durable response in only 4% of treated patients, and substantially prolongs the life of only an additional 3% of patients with advanced cancer (Smith et al., 1993, J. Natl. Cancer Inst. 85:1460-1474). Many of the current anticancer drugs are both cost-prohibitive, and present with major toxicity. Regarding the latter and depending on the drug or drug combination used, systemic chemotherapy may result in one or more toxicities including hematologic, vascular, neural, gastrointestinal, renal, pulmonary, otologic, and lethal. For example, tamoxifen has been used in women for 25 years to limit breast cancer recurrence. A trial launched in 1992 has shown that tamoxifen is not only effective as a therapeutic agent, but also has a very substantial benefit in cancer prevention (a breast cancer preventative agent). However, in that study, tamoxifen use was shown to have adverse effects in healthy women; i.e., an increased risk of developing uterine cancer or pulmonary blood clots (Science News, 1998, 153:228).
Plants are a valuable resource for the discovery and development of novel, naturally derived agents to treat cancer. Drugs that are currently used in cancer therapy were designed to perturb microtubule shortening (depolymerization) or lengthening (polymerization) (Compton, D. A., et al., (1999) Science 286:913-914). The centrosome, the major microtubule organizing center (MTOC) of the cell, is composed of two centrioles surrounded by the so-called pericentriolar material (PCM), which consists of a complex thin filament network and two sets of appendages (Paintrand, M. (1992) J Struct Biol 108:107-128). The main function of the centrosome is the nucleation of microtubules and the formation of bipolar spindles (Tanaka, T., et al., (1999) Cancer Res 58(17): 3974-85). Centrosomes and their associated microtubules direct events during mitosis and control the organization of animal cell structures and movement during interphase. Malignant tumors generally display abnormal centrosome profiles, characterized by an increase in size and number of centrosomes, by their irregular distribution, abnormal structure, aberrant protein phosphorylation, and by increased microtubule nucleating capacity in comparison to centrosomes of normal tissues (Lingle, W. L. et al., (1998) Proc Natl Acad Sci USA 95(6): 2950-5; Sato. N., et al., (1999) Clin Cancer Res 5(5):963-70; Pihan, G. A. et al., (1998) Cancer Res 58(17):3974-85; Carroll, P. E., et al., (1999) Oncogene 18(11): 1935-44; Xu, X., et al., (1999) Mol Cell 3(3):389-95; Brinkley, B. R., et al., (1998) Cell Motil Cytoskeleton 41(4):281-8; Doxsey, S. (1998) Nat Genet 20(2):104-6; Kuo, K. K., et al., (2000) Hepatology 31(1):59-64). Among the abnormalities, centrosome hyperamplification is found to be more frequent in a variety of tumor types (Carroll, P. E., et al., (1999) Oncogene 18; 18(11):1935-44; Hinchcliffe, E. H., et al., (1999) Science 283(5403):851-4; Xu, X., et al., (1999) Mol Cell 3(3):389-95; Weber, R. G., et al., (1998) Cytogenet Cell Genet 83:266-269).
A variety of drugs, such as paclitaxel, docetaxel, etoposide, vincristine, vinblastine, and vinorelbine, currently used in cancer therapy were designed to perturb microtubule polymerization (for review, see Jordan M A and Wilson L., Microtubules as a target for anticancer drugs. Nature Reviews Cancer 4:253-265 (2004)). They share a common mechanism of action of binding to tubulin, the molecule of which microtubules are composed. (Compton, D. A., et al., (1999) Science 286:913-914; Wilson, L., et al. Cell Struct. & Function 24:329-335 (1999)). At least six plant-derived anticancer agents have received FDA approval (e.g., taxol, vinblastine, vincristine, topotecan, etoposide, teniposide). Other agents are being evaluated in clinical trials (e.g., camptothecin, 9AC, and irinotecan).
Taxol, a diterpenoid originally isolated from the bark of the Pacific yew, Taxus brevifolia, is a powerful antimitotic agent that acts by promoting tubulin assembly into stable aggregated structures. (see review Kingston, D. G. I. Trends Biotechnol. 1994, 12, 222; Schiff, P. B.; Fant, J.; Horwitz, S. B. Nature, 1979, 277, 665). Taxol has shown tremendous potential as an anticancer compound. Indeed, it is now used for the treatment of refractory ovarian cancer, and clinical trials are encouraging for the treatment of breast, lung, head, and neck cancers. (Rowinsky, E. K.; Cazenave, L. A.; Donehower, R. C. J. Nat. Cancer Inst. 1990, 82, 1247; McGuire, W. P.; Rowinsky, E. K.; Rosenshein, N. B.; Grumbine, F. C.; Ettinger, D. S.; Armstrong, D. K.; Donehower, R. C. Ann. Int. Med. 1989, 11, 273; Forastiere, A. A., Semin. Oncol. Suppl. 3. 1993, 20, 56).
Vinca alkaloids, including the natural products vincristine and vinblastine and the semisynthetic derivatives vindesine and vinorelbine, are antimitotic drugs that are widely used in cancer treatment (Donehower R C and Rowinsky E K, Anticancer drugs derived from plants, in Cancer: Principles and Practice of Oncology. De Vita V T, Hellman S and Rosenberg S A eds. pp 409-417, JB Lippincott, Philadelphia. (1993)). Second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics differently from vinblastine, a first generation Vinca alkaloid which strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events (Ngan V. K. et al., Mol Pharmacol. 60(1):225-232 (2001)).
Chemopreventive agents being investigated for the ability of reducing the amount of pre-cancerous cells in the lungs of smokers and ex-smokers include ACAPHA, a combination of six botanicals (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus and Dioscorea bulbifera) which has been used for disease prevention in China for centuries. Under a US National Cancer Institute grant, the British Columbia Cancer Agency (Canada) is leading an international consortium in carrying out the phase II clinical trials of ACAPHA.
Cancer implicates several important signal pathways in the cell such as growth control pathways (20 percent of the known types of cancer, including some breast and brain cancers). The same pathways also play key roles in the autoimmune response signal pathway, so inhibitors of the pathway have potential use as immuno-suppressive and anti-inflammation drugs. Combining drug compounds with certain naturally occurring proteins have been shown as an alternative way to produce improved pharmaceuticals, particularly immuno-suppressive, anti-inflammation and anti-cancer drugs. (Briesewitz R, Ray G T, Wandless T J, Crabtree G R., Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces. Proc Natl Acad Sci USA. (1999) March 2; 96(5):1953-1958).
There is a need for a relatively cost-effective and efficient method for preventing tumors and inhibiting growth of tumors, which additionally ameliorates the toxicity generally associated with systemic chemotherapy. Anticancer compositions comprising Gynostemma pentaphyllum extract, Camellia sinensis (green tea) and Crataegus pinnatifida (hawthorn berries) and a method of making the same is the subject of U.S. Pat. Nos. 5,910,308 and 6,168,795 (DJang).